Phosphoinositide 3-kinases (PI3Ks) is a enzyme which specifically catalyze the phosphorylation of 3rd position hydroxyl in phosphatidylinositol (PI) and its derivatives, and produce the phosphatidylinositol-3,4,5-triphosphate (PI3P) which serve as the second messenger. Signal transduction mediated by PI3Ks involves in regulations of several cell functions such as cell division, differentiation, apoptosis, metabolism, angiogenesis, and plays an important role in the activation of a variety of cell biological functions. Studies in recent years have shown that signaling pathways consisted of PI3Ks and the downstream molecular protein kinase B (PKB or Akt) are closely associated with the genesis and development of cancer, regulating tumor cell proliferation, apoptosis and promoting tumor angiogenesis, etc.
Quinazolinone compounds and derivatives thereof are a class of inhibitors for Phosphoinositide 3-kinase. A series of quinazoline derivatives has been disclosed in WO03035075 and WO2005113556. Among them the compound GS-1101, of which the chemical name is (S)-2-(1-(9H-purin-6-yl-amino)propyl)-5-fluoro-3-phenyl quinazoline-4(3H)-ketone, is a selective PI3K kinase inhibitor, and it can be used in the treatment of cancer and cell proliferative diseases, and other related diseases. At present, the compound is in the Phase III clinical trials of treating chronic lymphocytic leukemia and non-Hodgkin lymphomas.
Phosphoinositide 3-kinase (PI3K) is one of the important targets for the development of new anti-tumor drugs. However, except for rapamycin and homologs, the research progress of inhibition of PI3K signal transduction pathway is relatively slow, especially the development of specific inhibitors for PI3K subtypes (such as type I PI3K including p110α, p110β, p110δ, etc.) is still very challenging.
Therefore, there is still a need in the art to develop compounds having PI3K kinase inhibitory activity or better pharmacodynamic/pharmacokinetics properties.